PROJECT SUMMARY Nonalcoholic fatty liver disease (NAFLD) affects an estimated 30% of the adult U.S. population1-3. Several studies suggest type 2 diabetes mellitus (T2DM) is a strong independent risk factor for NAFLD progression to NASH and liver fibrosis4-13 and confers an increased risk of hepatocellular carcinoma14-18. However, current AASLD NAFLD practice guidelines state routine screening for NAFLD in high-risk groups such as the T2DM population ?is not advised at this time because of uncertainties surrounding diagnostic tests and treatment options, along with lack of knowledge related to long-term benefits and cost-effectiveness of screening?19. Here, we propose to use advanced magnetic resonance imaging (MRI) to study and monitor NAFLD and fibrosis in a prospective cohort of T2DM patients. Our overarching goal is to collect the necessary evidence to make an informed decision on whether screening the T2DM population for advanced fibrosis due to NAFLD is advisable and cost-effective. We will also define the best screening approach, balancing diagnostic accuracy and availability with cost. Our group has developed and clinically validated two advanced magnetic resonance imaging (MRI) modalities for non-invasive assessment of liver fat and fibrosis: MRI Proton Density Fat Fraction (MRI-PDFF) and MR Elastography (MRE). Using these advanced technologies, we will accurately phenotype T2DM patients to assess their risk of advanced fibrosis and monitor rates of NAFLD progression in this population. To achieve our goal, our specific aims are: Aim 1: Test the hypothesis that MRE and VCTE can reliably and non-invasively detect the presence of advanced fibrosis due to NAFLD in T2DM patients. To evaluate diagnostic approaches for screening the T2DM population, here we will use MRI-PDFF and MRE to accurately estimate the prevalence of NAFLD and advanced fibrosis, respectively. The primary outcome will be advanced fibrosis, as defined by MRE ? 3.63 kPa, with additional confirmation by liver biopsy. MR-based assessments will be used as reference standards to identify corresponding cut-off values for their transient elastography counterparts, VCTE and CAP. Aim 2: Identify risk factors and biomarkers for rapid fibrosis progression in the T2DM population To define which T2DM patients are most likely to show rapid fibrosis progression, we will longitudinally follow a subset of study participants. We hypothesize that higher liver fat content at baseline (>15.7%) associates with higher rate of liver stiffness progression in the T2DM population. We further hypothesize that those with higher liver stiffness have a greater risk of progression, as defined as MRE > 4.67 kPa, or cirrhosis. We will also explore risk factors and imaging- and serum-based biomarkers that may help identify fast progressors. Aim 3: Test the hypothesis that screening T2DM patients for advanced fibrosis is cost-effective. Here, we will identify whether, when and for which T2DM subgroups NAFLD screening benefits outweigh the risks.